ABSTRACT (Surrogate Marker Core) The development and application of biomarkers to neurodegenerative diseases has become increasingly important to clinical practice and therapeutic trials. While substantial progress has been made at the basic science level in understanding the pathophysiology of HIV-Associated Neurocognitive Disorders (HAND), there are currently significant limitations in our ability to predict the onset and/or trajectory of cognitive impairment, and to accurately determine the effects of therapeutic interventions on biological functions. Part of the difficulty in identifying clinically useful surrogate measures for HAND lies in the heterogeneity of this clinical population, the mixture of risk factors that contribute to HAND, and disparities in markers when using cross sectional compared with longitudinal associations. To help circumvent these difficulties we have developed a diverse set of surrogate markers to measure multiple aspects of immune activation, energy metabolism, cellular activation and damage. These biological measures are combined with clinical and demographic characteristics using a combination of parametric and non-parametric statistical approaches that provide a powerful means to identify groups of surrogate measures that define patients in accordance with clinical and cognitive characteristics. These surrogate markers will be used as outcome measures for the mechanistic studies proposed in project 1, in vivo studies with EkoHIVmice in project 2 and for CSF and plasma samples obtained from the clinical trial in project 3.